In vivo clonal expansion and phenotypes of hypocretin-specific CD4+ T cells in narcolepsy patients and controls

Wei Jiang; James R Birtley; Shu-Chen Hung; Weiqi Wang; Shin-Heng Chiou; Claudia Macaubas; Birgitte Kornum; Lu Tian; Huang Huang; Lital Adler; Grant Weaver; Liying Lu; Alexandra Ilstad-Minnihan; Sriram Somasundaram; Sashi Ayyangar; Mark M Davis; Lawrence J Stern; Elizabeth D Mellins

doi:10.1038/s41467-019-13234-x

In vivo clonal expansion and phenotypes of hypocretin-specific CD4⁺ T cells in narcolepsy patients and controls

Nat Commun. 2019 Nov 20;10(1):5247. doi: 10.1038/s41467-019-13234-x.

Authors

Wei Jiang^{1

2}, James R Birtley^{3

4}, Shu-Chen Hung^{5

6}, Weiqi Wang⁷, Shin-Heng Chiou⁸, Claudia Macaubas^{5

6}, Birgitte Kornum⁹, Lu Tian¹⁰, Huang Huang⁸, Lital Adler^{5

11}, Grant Weaver³, Liying Lu³, Alexandra Ilstad-Minnihan⁵, Sriram Somasundaram⁵, Sashi Ayyangar⁵, Mark M Davis^{6

8

12}, Lawrence J Stern³, Elizabeth D Mellins^{13

14}

Affiliations

¹ Department of Pediatrics-Human Gene Therapy, Stanford University School of medicine, Stanford, CA, 94305, USA. [email protected].
² Stanford Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA. [email protected].
³ Department of Pathology, University of Massachusetts Medical School, Worcester, MA, 01655, USA.
⁴ UCB Pharma, Slough, SL13WE, UK.
⁵ Department of Pediatrics-Human Gene Therapy, Stanford University School of medicine, Stanford, CA, 94305, USA.
⁶ Stanford Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
⁷ Human Immune Monitoring Center, Stanford University School of Medicine, Stanford, CA, 94305, USA.
⁸ Institute for Immunity, Transplantation and Infection, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
⁹ Danish Center for Sleep Medicine, Department of Clinical Neurophysiology, Rigshospitalet, 2600, Glostrup, Denmark.
¹⁰ Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, 94305, USA.
¹¹ Department of Biological Regulation, Weizmann Institute of Science, Rehovot, 7610001, Israel.
¹² Howard Hughes Medical Institute, Stanford University, Stanford, CA, 94305, USA.
¹³ Department of Pediatrics-Human Gene Therapy, Stanford University School of medicine, Stanford, CA, 94305, USA. [email protected].
¹⁴ Stanford Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA. [email protected].

Abstract

Individuals with narcolepsy suffer from abnormal sleep patterns due to loss of neurons that uniquely supply hypocretin (HCRT). Previous studies found associations of narcolepsy with the human leukocyte antigen (HLA)-DQ6 allele and T-cell receptor α (TRA) J24 gene segment and also suggested that in vitro-stimulated T cells can target HCRT. Here, we present evidence of in vivo expansion of DQ6-HCRT tetramer⁺/TRAJ24⁺/CD4⁺ T cells in DQ6⁺ individuals with and without narcolepsy. We identify related TRAJ24⁺ TCRαβ clonotypes encoded by identical α/β gene regions from two patients and two controls. TRAJ24-G allele⁺ clonotypes only expand in the two patients, whereas a TRAJ24-C allele⁺ clonotype expands in a control. A representative tetramer⁺/G-allele⁺ TCR shows signaling reactivity to the epitope HCRT_87-97. Clonally expanded G-allele⁺ T cells exhibit an unconventional effector phenotype. Our analysis of in vivo expansion of HCRT-reactive TRAJ24⁺ cells opens an avenue for further investigation of the autoimmune contribution to narcolepsy development.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autoimmunity / genetics
Autoimmunity / immunology*
CD4-Positive T-Lymphocytes / immunology*
Case-Control Studies
Cell Proliferation
Crystallography, X-Ray
Drosophila
HLA-DQ Antigens / genetics
HLA-DQ Antigens / immunology
Humans
Immunoglobulin Joining Region / genetics
Narcolepsy / genetics
Narcolepsy / immunology*
Orexins / immunology*
Peripheral Tolerance
Phenotype
Receptors, Antigen, T-Cell, alpha-beta / genetics
Receptors, Antigen, T-Cell, alpha-beta / immunology

Substances

HCRT protein, human
HLA-DQ Antigens
HLA-DQ6 antigen
Immunoglobulin Joining Region
Orexins
Receptors, Antigen, T-Cell, alpha-beta

Abstract

Publication types

MeSH terms

Substances

Grants and funding